Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course

Daniel Delev,Dietmar Pfeifer,Annette Gaebelein,Jürgen Beck,Pamela Franco,Alexander Grote,Karam Daka,Dieter Henrik Heiland,Oliver Schnell,Horst Urbach,Albert J Becker,Sabrina Heynckes,Marco Prinz,Irina Mader

doi:10.1038/s41598-019-56146-y

Abstract

Long-term epilepsy-associated tumors (LEATs) represent mostly benign brain tumors associated with drug-resistant epilepsy. The aim of the study was to investigate the specific transcriptional signatures of those tumors and characterize their underlying oncogenic drivers. A cluster analysis of 65 transcriptome profiles from three independent datasets resulted in four distinct transcriptional subgroups. The first subgroup revealed transcriptional activation of STAT3 and TGF-signaling pathways and contained predominantly dysembryoplastic neuroepithelial tumors (DNTs). The second subgroup was characterized by alterations in the MAPK-pathway and up-stream cascades including FGFR and EGFR-mediated signaling. This tumor cluster exclusively contained neoplasms with somatic BRAFV600E mutations and abundance of gangliogliomas (GGs) with a significantly higher recurrence rate (42%). This finding was validated by examining recurrent tumors from the local database exhibiting BRAFV600E in 90% of the cases. The third cluster included younger patients with neuropathologically diagnosed GGs and abundance of the NOTCH- and mTOR-signaling pathways. The transcript signature of the fourth cluster (including both DNTs and GGs) was related to impaired neural function. Our analysis suggests distinct oncological pathomechanisms in long-term epilepsy-associated tumors. Transcriptional activation of MAPK-pathway and BRAFV600E mutation are associated with an increased risk for tumor recurrence and malignant progression, therefore the treatment of these tumors should integrate both epileptological and oncological aspects.

Highlights

Long-term epilepsy-associated tumors (LEATs) represent mostly benign brain tumors associated with drug-resistant epilepsy
The optimal number of clusters was determined by using a partitioning around medoids (PAM) unsupervised clustering and achieved the highest average silhouette width at four clusters (C1–C4) (Fig. 1b)
Since BRAF mutations and other oncogenic drivers lead to activation of MAPK and AKT-mTOR pathways, our goal was to examine to what extent MAPK or AKT-mTOR pathway activation was associated with poor disease course

Summary

Introduction

Long-term epilepsy-associated tumors (LEATs) represent mostly benign brain tumors associated with drug-resistant epilepsy. The second subgroup was characterized by alterations in the MAPK-pathway and up-stream cascades including FGFR and EGFR-mediated signaling This tumor cluster exclusively contained neoplasms with somatic BRAFV600E mutations and abundance of gangliogliomas (GGs) with a significantly higher recurrence rate (42%). Transcriptional activation of MAPK-pathway and BRAFV600E mutation are associated with an increased risk for tumor recurrence and malignant progression, the treatment of these tumors should integrate both epileptological and oncological aspects. We present a comprehensive clinical, pathological and molecular analysis aiming at the more precise differentiation of long-term epilepsy-associated tumors and better understanding of their oncological background. We performed transcriptional analysis identifying four distinct molecular subgroups among histologically diagnosed GGs, DNTs. and PXAs. Gene Set Enrichment Analysis (GSEA) identified genetic abnormalities characteristic for each subgroup helping to stratify those patients, who carry a higher risk for tumor progression. The transcriptional results were validated by immunohistochemistry examinations of recurrent epilepsy-associated glioneuronal tumors from the local patient database

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